Oxidative metabolism in heart regeneration: friend or foe?

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Cardiovascular disease is the leading cause of death worldwide. This can be partially attributed to the inability of the human heart to regenerate lost cardiac tissue. Upon myocardial infarction billions of cardiomyocytes die and the necrotic tissue is then replaced by a non-contractile fibrotic scar which will eventually lead to the development of heart failure and death. Consequently, identifying pathways which can lead to successful heart regeneration has immense therapeutic potential.In contrast to humans, and adult mammals in general, zebrafish maintain the ability to regenerate lost cardiac tissue throughout their adult life. As a result, the are an excellent model to identify pathways which drive cardiac regeneration. Nevertheless, the regenerative capacity of several wild type zebrafish strains is highly variable. During my DPhil I will be exploiting those intra-species differences to identify novel pathways which are responsible for successful heart regeneration.Through this comparative approach I have identified a previously underappreciated role of oxidative metabolism in the regenerative process. Contrary to what was previously believed, successful heart regeneration appears to be dependent on an upregulation of oxidative metabolism genes during its late stages. This process seems to be linked to the expression of embryonic myosin markers. Through my DPhil I intend to further understand the interplay between metabolism, gene expression and cardiomyocyte re-differentiation through the use of RNAseq, proteomics and metabolomics. Additionally, comparison between the regenerative surface fish and non-regenerative cavefish (Astyanax mexicanus) will reveal whether the mechanisms identified in zebrafish are conserved through evolution in other species.Furthermore, through comparison of P1 to P7 neonatal mice heart regeneration I will validate the expression of oxidative phosphorylation in the regenerating P1 heart and characterise its role in the context of cardiomyocyte re-differentiation. Additionally, I intend to pharmacologically modulate oxidative metabolism in adult mice to explore any therapeutic potential of these metabolic pathways to induce heart regeneration in the mammalian heart.In conclusion, this project aims at the characterisation of oxidative phosphorylation as a factor which promotes heart regeneration.